It is time to individualize anti-CD20 therapies in multiple
sclerosis
Jagannadha Avasarala, MD, PhD
Department of Neurology, University of Kentucky Medical Center and
Kentucky Neuroscience Institute, Lexington, KY 40536, USA
Correspondence:
Jagannadha Avasarala, MD, PhD
Professor of Neurology
Director, Comprehensive MS Center
Department of Neurology
University of Kentucky Medical Center
Kentucky Neuroscience Institute
740 S Limestone
Lexington, KY 40536
WC: 1365
The first and only self-administered CD20 depleting therapy for
relapsing forms of multiple sclerosis (MS), ofatumumab (Kesimpta), was
approved by the FDA in August 2020. It is an immunoglobulin class G1
kappa monoclonal antibody (Mab) that selectively binds to an epitope on
the cell surface protein, CD20. The CD20 is a transmembrane cellular
protein that is a therapeutic target in B-cell malignancies and is
expressed in over 95% of B-cell lymphocytes throughout their
development but is absent in hematopoietic stem cells. In the IV
administered form, Arzerra/ofatumumab, FDA-approved for use in patients
with previously untreated chronic lymphocytic leukemia (CLL) in October,
2009, B-cell depletion in the peripheral blood was persistent after six
months following the last dose. In vitro, ofatumumab induces
complement-dependent cytotoxicity (CDC) and antibody-dependent cellular
cytotoxicity (ADCC) which contribute to depletion of CD20 cells in
peripheral blood.
According to the package insert , the recommended dosing regimen
for Kesimpta/ofatumumab in RMS is a monthly dose of 20 mg, given
subcutaneously, after an initial dosing regimen protocol. Thepackage insert for any drug is a document that was first
developed in 1966, amended in 2006 and carries potential legal weight;
it also includes data supplied by the manufacturer that is
evaluated/approved by the Food and Drug Administration (FDA). In
clinical trials leading up to the approval of the drug, approximately
1500 patients with RMS received ofatumumab. In study 1 (NCT02792218) and
study 2 (NCT02792231), 1882 patients with RMS were randomized, 946 of
whom were treated with ofatumumab for a median duration of 85 weeks;
about 33% of patients receiving ofatumumab were treated for up to 120
weeks. In both studies, ofatumumab administration resulted in a
reduction of CD19+ B-cells to below the LLN in 77.0% and 78.8% of
patients, respectively, one week after treatment initiation, and in
95.0% and 95.8% of patients, respectively, two weeks after treatment
initiation. To follow how B-cell depletion occurs, assays for CD19+
B-cells were used because the presence of the drug interferes with the
CD20 assay.
In both studies, at week 12, 99.3% to 99.5% of patients had CD19+
B-cell counts below LLN. The CD19+ B-cell counts remained below LLN for
approximately 97% of patients in Study 1 and 92% of patients in Study
2 from 12 weeks through 120 weeks while on treatment. Modeling and
simulation for B-cell repletion corroborates these data, predicting
median time to B-cell recovery of 40 weeks post-treatment
discontinuation.
Comparative pharmacokinetic data for Arzerra/ofatumumab shows that owing
to depletion of B cells that follows each subsequent infusion, drug
clearance is significantly decreased as compared to its clearance after
the first infusion of the drug. This is attributed to its clearance by
both a target-independent and a B-cell mediated route. The initial
dosing for Arzerra is 300 mg/kg followed by seven weekly and four
monthly infusions of 2000 mg/kg per dose. The Cmax were
40% higher and area under curve (AUC) were 60% higher after the
8th infusion than after the 4thinfusion. This points to decreased drug clearance when B cell
populations are depleted. One of the most consistent findings in animal
and human studies is the variability of depletion seen with anti-CD 20
MAbs in different individuals even when treated with the same
dose1. Interestingly, depletion in the same individual
tends to be consistent in different tissues, suggesting that individual
characteristics are probably important.
For Kesimpta/ofatumumab, a study of bioequivalence before initiation of
the maintenance phase, total CD19+ B-cell levels below the defined
threshold of 10 cells/µL were achieved in 94% of patients starting at
week 4 and in 98% of patients at week 12. B-cell repletion data from
RMS clinical studies indicate B-cell recoveries over the LLN in about
50% of patients in 24-36 weeks post-treatment discontinuation. In a
study that provided class I evidence, the MIRROR
study2, the authors noted a dose-dependent depletion
of B cells, (Figure 1) with the most effect for the 60 mg dose
administered every 12 weeks (the recommended dose is 20 mg q weekly, per
the package insert for Kesimpta) and in this cohort, the B cell
reconstitution ranged from 85-777 days (323.4 days, mean). The effect of
cumulative or subsequent dosing on B cell depletion was not studied in
the MIRROR study. Individualized treatment schedules need to be
developed given the wide range of B cell repopulation kinetics, i.e.,
85-777 days.
Reconstitution of B cells is complex and cells that repopulate have a
different immunological profile. The first wave of repopulating B cells
are immature B cells (CD38high, IgD+, CD10+,
CD24high), and the immunoglobulin receptors are not
yet somatically mutated3. Additionally, the number of
naive B cells increase, and they predominate in the peripheral blood B
cell pool. CD27+ memory B cells show a slow and delayed repopulation,
but their numbers stay significantly reduced (<50%) compared
to baseline3. Repopulation occurs mainly with naïve B
cells and transitional B cells similar to that seen after bone marrow
transplantation4. In a recent
publication5, repopulating B cells after anti-CD20
therapy were shown to display a phenotype that is transitional and
naïve, with a reduction in memory B cells. Reappearing B cells showed
activation of CD25, CD69, and expressed higher levels of costimulatory
CD40 and CD86 markers. Most importantly, B-cell repopulation kinetics
display both high inter-and intra-individual variance and a higher body
mass index (BMI) may be associated with faster repopulation
rates6. One course of treatment with Rituxan, the
original CD20 depleting drug, was followed by B-cell repopulation of the
peripheral blood starting usually within 6-9 months - but it can take
several months or even years for total B-cell numbers recover to
pretreatment levels. Hence, re-dosing that is not based on B cell
kinetics, either qualitative or quantitative, or both, is not based on
evidence.
In studies that have investigated the depletion of CD20-expressing B
cells in solid tissues, it has been shown that depletion is significant
but not complete, with bone marrow and spleen being more easily depleted
than lymph nodes7. Depletion of B cells is thought to
include not only the total drug dose administered and distribution into
various tissues, but also B-cell intrinsic and microenvironment factors
influencing recruitment of effector mechanisms and antigen and effector
modulation. The degree of B cell depletion varies between individuals
even for the same dosage but does not have significant variation in the
same individual suggesting that individual factors are important in
determining the final extent of depletion, a finding ideal for designing
individualized therapy in MS. Furthermore, CD20 depletion is associated
with immunoglobulin - IgM and then IgA and IgG hypogammaglobulinaemia in
some cases, predisposing patients to a small but increased risk of
severe infections8.
It is unclear why Kesimpta/ofatumumab needs to be dosed monthly since
there are no data to support that rationale. Most importantly, no formal
review of Kesimpta/ofatumumab for MS is available through the Center for
Drug Evaluation and Research (CDER) and the FDA does not have
pharmacokinetic (PK) data published on its website for this product.
Absent a formal review by CDER, dosing schedules for Kesimpta/ofatumumab
are probably extrapolated from a combination of assessment of ofatumumab
(Arzerra) by CDER and the MIRROR study findings - a clear rationale is
not provided. Data for Arzerra/ofatumumab is available from that
product’s review in the past, however. Although the depletion of B-cells
in the peripheral blood had a measurable pharmacodynamic effect for
Arzerra/ofatumumab, it was not directly correlated with the depletion of
B cells in solid organs and the effect of B-cell depletion was not
linked to clinical response (package insert, Arzerra). If clinical
responsiveness is not related to B-cell depletion in CLL, how sure are
we that the depletion of CD20 cells in MS secondary to
Kesimpta/ofatumumab, drives the clinical response ?
In conclusion, an individualized dosing approach to anti-CD20 therapies
is long overdue because 1) repopulation of B cells shows high intra and
inter-individual variance, 2) naïve B cells are the predominant cell
type in repopulated cells 3) B cell depletion may be dependent, in part,
on BMI, 4) the clearance of Arzerra/ofatumumab requires the existence of
B cell populations with subsequent dosing(s) and 5) increased risk of
infections associated with hypogammaglobulinemia observed in patients
using 6 monthly dosing of anti-CD20 drugs. Why then are dosing schedules
for anti-CD20 drugs not personalized ?
Conflict of interest: None